Importantly, how commensals contribute to the expression
of these enzymes and metabolism of vitamin A remains unknown. Another important question is the timing necessary for DCs migrating in the GALT to acquire RA from epithelial cells and how these processes can be modified during infection. How RA contributes to oral tolerance, and at the same time protective immunity in the GI tract, also remains to be addressed. One possibility is that RA favours the induction of Tregs in the absence of secondary signals but enhances effector responses following exposure to inflammatory mediators. Treg populations require not only appropriate conditions for their induction, but also for their upkeep, particularly when confronted with an inflammatory environment. Very recently it has been shown that, in the gut, myeloid cell-derived IL-10 plays a crucial role in maintaining functional Treg activity by stimulating Caspase activity assay IL-10R directly on FoxP3+ Tregs and allowing them to play a fully protective role in the prevention of colitis [45]. Thus, in the absence of either innate IL-10 production, or IL-10R on Tregs, these cells lose
the ability to block colitogenic effector T cells from causing inflammatory disease, and indeed succumb themselves to the inflammatory process by switching to the production of IFN-γ[45]. Hence, IL-10 is important for the maintenance of Treg activity and can be Phospholipase D1 pivotal at the tipping-point between regulation check details and inflammation. The regulation of Treg activity between the gut and the periphery is also of special interest, as IBD in humans may affect extraintestinal organs in up to 36% of cases [46]. IBD-related extraintestinal disorders are not specific to IBD. They can be classified into reactive manifestations dependent directly upon intestinal disease. The often co-existing presentation in the same patient points towards common underlying pathomechanisms that may involve enteric flora activating the immune system to turn against bacterial antigens and, based
on cross-reactivity, against intestinal antigens and antigens in extraintestinal organs (‘molecular mimicry’). A separate subset of IBD patients shows an increased frequency of other common autoimmune diseases that manifest mainly independently of the bowel disease. This may thus reflect susceptibility to autoimmunity in general. The complex relationship between intestinal and extraintestinal manifestations in IBD is also reflected by the complex multi-genetic control reported in animal models of IBD; genetic loci regulating intestinal and extra-intestinal manifestations are largely but not exclusively different [47]. The appearance of GI parasites is a major challenge to the discriminatory powers of the immune system, and one which in evolutionary time has been played out countless times.